Following traumatic or mechanically induced axonal degeneration in the peripheral nervous system, axonal regeneration ensues, resulting in functional recovery. However, the rate of axonal elongation (3-4 mm/day) is slow. Consequently, recovery is measured in weeks or months, depending upon the distance between the site of injury and the target tissue. Therapies that speed regeneration over long distances would be highly beneficial to patients and would significantly reduce health care costs.
The immunosuppressant drug FK506 (USAN tacrolimus; Prograf®) speeds functional recovery and axonal regeneration in the rat in a dose-dependent manner following a sciatic nerve crush lesion (Gold et al., J. Neurosci. 15:7505-7516, 1995; Gold et al., Restor. Neurol. Neurosci. 6:287-296, 1994). FK506 was shown to stimulate neuritic outgrowth in a rat pheochromocytoma cell line in a concentration-dependent manner (Lyons et al., Proc. Natl. Acad. Sci. USA 91:3191-3195, 1994).
Systemic administration of two synthetic FK506 analogs that bind FKBP-12 but that do not inhibit calcineurin activity (and which are not immunosuppressants) increases the size of myelinated fibers (Steiner et al., Nature Medicine 3:1-8, 1997; Steiner et al., Proc. Natl. Acad. Sci. USA 94:2019-2024, 1997). U.S. Pat. No. 5,654,332 (Armistead et al.) discusses immunosuppressive FK506 analogs that bind FKBP12 and that are said to stimulate neurite outgrowth in the presence of NGF. It was stated that the neurotrophic activity of these FKBP12 binding compounds “is directly related to their affinity for FKBP12 and their ability to inhibit FKBP12 rotomase activity” (id. at col. 7, lines 47-50).
It has been reported that androgens and estrogens stimulate facial nerve regeneration in hamsters (Jones, “Androgenic enhancement of motor neuron regeneration,” In: Luine and Harding, eds., Hormonal Restructuring of the Adult Brain, Ann. N.Y. Acad. Sci. 85:141-164, 1994; Tanzer and Jones, Exp. Neurol. 146:258-264, 1997).